Project summary Significance: Antibiotic administration during pregnancy and has been demonstrated to alter microbiome diversity and further is associated with an increased risk of childhood asthma. It is unknown, however, whether timing, spectrum of antibiotics, and cumulative exposure have a differential role in the development of asthma. Specific Aims: We hypothesize that greater cumulative exposure of certain groups of antibiotics during definable critical susceptible period(s) of pregnancy and infancy increases the risk of childhood asthma. To identify the critical time period(s) when cumulative exposure of certain antibiotics increases the risk of childhood asthma, we will determine 1) whether timing, spectrum, and cumulative exposure of antibiotics during pregnancy and infancy are associated with an increased risk of childhood asthma; 2) whether combinations of the susceptible time period(s), spectrum of antibiotics, and cumulative exposure during pregnancy and infancy are associated with an increased risk of childhood asthma. Research Design: We will conduct a population based cohort study using the Tennessee Medicaid population, a subset of the established PRIMA cohort (Prevention of RSV: Impact on Morbidity and Asthma; R01 HS018454-01 PI Hartert) of 148,700 mother-child dyads. In aim 1, we will estimate the critical time periods, the spectrum of antibiotic activity, and the cumulative exposure individually on the risk of childhood asthma. In aim 2, the combination of timing, spectrum, and cumulative exposure of antibiotics on the risk of childhood asthma will be analyzed. In all aims, subgroup analyses by maternal asthma status will be conducted to differentiate the antibiotic effect from genetic predisposition to asthma. Impact: As a lifelong chronic disease, there is currently no primary prevention strategy available for asthma. Antibiotics are widely used to treat infection. Our results of identification of critical exposure period(s), safe minimum duration of antibiotics at each development stage of pregnancy and infancy, and ?lower risk? antibiotics are of great clinical value. Findings of the study will provide clinicians, patients and policy makers additional information in decision making of antibiotic use.